The University of Texas M. D. Anderson SPORE in Pancreatic Cancer is focused on translating recent observations in molecular biology, cellular signaling, and DNA repair to patient care. This application outlines a strong institutional effort to foster research on the etiology, biology, and treatment of human pancreatic cancer that will translate basic research findings into concrete clinical research protocols involving pancreatic cancer patients. To accomplish this goal, five projects are proposed: Project 1 - A Novel Therapeutic Gene, p202, and its Potential in Pancreatic Cancer Therapy seeks to credential a specific new protein target that is applicable to pancreatic cancer because of its ability to inhibit the activity of NF-KappaB. The successful development of this strategy will lead to direct therapeutic application using a gene transfer approach. Project 2 - Role of COX-2 in Pancreatic Cancer Progression and Therapy will explore the mechanism of Cox-2 overexpression in pancreatic cancer. This project will specifically examine the hypothesis that EGF-EGF receptor interactions control PLA2 and COX2 expression in pancreatic cancer cells and that COX-2 regulates an important cell survival pathway. To address this issue in patients, a clinical trial entitled "Assessment of Biological Markers of Response to Treatment with Celecoxib and OSl 774 in Patients with Advanced Pancreatic Cancer" is proposed. Project 3 - NFkB Signaling Pathways in Pancreatic Cancer Biology &Therapy explores the biochemical effects and biologic consequences of a series of strategies to inhibit the EGFR - Akt - NFKappaB signaling pathway. Each approach tested has potential clinical relevance to pancreatic cancer. To clinically assess the impact of EGFR inhibition, a clinical trial entitled "Phase II Randomized Trial of Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Cetuximab vs. Cetuximab Plus Gemcitabine in Patients with Advanced Pancreatic Cancer" is proposed. Project 4 - Regulation of Pancreatic Cancer Angiogenesis and Metastasis by Transcription Factor Sp1 will examine the hypothesis that disregulated expression and activation of Sp1 is responsible for aberrant expression of multiple angiogenic molecules that generates the angiogenic phenotype and sustains tumor growth and metastasis. Project 5 - DNA Repair as a Risk Factor for Pancreatic Cancer tests the hypothesis that DNA repair capacity is a risk factor for pancreatic cancer, and that polymorphisms in DNA repair and cell cycle genes modulate the efficiency of DNA repair capacity thereby increasing individual risk of pancreatic cancer or response to therapy. Data from two clinical trials in patients with resectable pancreatic cancer will examine the effect of DNA repair on patient survival following multi-modality therapy. To support these efforts, two Cores are proposed: Core - Biostatistics and Information Management will provide biostatistical support for the design and analysis of all Projects and clinical trials conducted through the SPORE. Core - Tissue Procurement and Distribution will facilitate the acquisition and distribution of pancreatic cancer and normal tissue to all SPORE Projects and collaborators. This Core will also evaluate and distribute all tumor biopsies and blood obtained from the clinical trials. We believe that our well-developed program will provide a significant and sustained impact on pancreatic cancer translational research and identify new research opportunities that will have an impact in reducing pancreatic cancer incidence and mortality.